A commercially attractive process for the preparation of nizatidine should yield the product in a highly pure form, or at least in an easily purifiable form. This is particularly advantageous for the last step in a pharmaceutical product synthesis. One general approach to this is the design of a process in which the immediate precursor compound of the final pharmaceutical product differs therefrom, to a significant degree, in respect of acidity or basicity, so that acid/base reactions can be used in separating final product from unreacted precursor.
Nizatidine has Bronsted basicity, i.e. basicity towards protons, derived essentially from the dimethylamino group on the thiazole ring acting in concert with the nitrogen of the thiazole ring. If, therefore, in the final synthetic step of making nizatidine, there is used a precursor which is much more weakly basic than nizatidine, separation of the nizatidine products from the precursor and other by-products can be achieved using simple acid/base reactions and extractions. Such processes are rugged, in the sense that they can be readily scaled up and are relatively insensitive to parameter variables.
U.S. Pat. No. 5,541,335 Manning, issued Jul. 30, 1996, discloses one such process. According to this patent, nizatidine is prepared by reacting N-[2-[[[2-(hydroxymethyl)-4-thiazolyl]methyl]thio]ethyl]-N'-methyl-2-nitro -1,1-ethenediamine, of formula: ##STR1## with excess dimethylamine and an (N,N-dimethylamino)phophonium halide such as (N,N-dimethylamino)triphenylphosphonium bromide. The hydroxymethyl reactant has a much lower basicity than the dimethylamino product, nizatidine, thereby allowing ready separation and purification of the product mixture. However, the phosphonium reagents and the solvents proposed for use in this process are complex and costly.
U.S. Pat. No. 5,574 054 Kitagawa et al. (Zeria), issued Nov. 12, 1996 discloses quaternary ammonium salts and nizatidine salts of nizatidine and the like, for use in treating gastrointestinal disorders. In one process for preparing these compounds N-[2-[[[2-(hydroxymethyl)-4-thiazolyl]-methyl]thio]ethyl]-N'-methyl-2-nitr o-1,1-ethenediamine is first prepared and is then chlorinated with phosphorus oxydichloride to the corresponding 2-chloromethyl compound. Preparation of corresponding acid residue compounds, e.g. by reaction with methanesulfonic acid chloride and toluene sulfonic acid chloride, is also suggested.